title: Increased oxidative metabolism and neurotransmitter cycling in the brain of mice lacking the thyroid hormone transporter SLC16A2 (MCT8).
abstract: Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-(13)C) glucose and brain extracts prepared and analyzed by (13)C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.
authors.affiliation: Instituto de Investigaciones Biomedicas, Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, Madrid, Spain ; CRUK, Cambridge Institute and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Tiago B
authors.initials: TB
authors.lastname: Rodrigues
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Ceballos
authors.forename: Carmen
authors.initials: C
authors.lastname: Grijota-Martínez
authors.forename: Barbara
authors.initials: B
authors.lastname: Nuñez
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Sebastian
authors.initials: S
authors.lastname: Cerdán
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morte
authors.forename: Juan
authors.initials: J
authors.lastname: Bernal
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004789:Enzyme Activation; D055786:Gene Knockout Techniques; D006980:Hyperthyroidism / Q000378:metabolism; D007453:Iodide Peroxidase / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D027501:Monocarboxylic Acid Transporters; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010084:Oxidation-Reduction; D027981:Symporters; D013963:Thyroid Hormones / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D018377:Neurotransmitter Agents; D027981:Symporters; D013963:Thyroid Hormones; D000097564:Iodothyronine Deiodinase Type II; C484257:Slc16a2 protein, mouse